Human and rodent carcinogens (trans-species carcinogens) often demonstrate similar organotropic patterns of neoplasia. Understanding the role of p53 haploinsufficieny (i.e. synchronization of critical genetic events) in carcinogen specific induction of tissue specific neoplasia in genetically altered rodents is critical to determining the phenotypic similarities between humans and rodents. Rodent model systems have the advantage of being subject to experimental investigation. Only where relevant mechanisms between human and rodents can be investigated are we able to remove some of the uncertainty of extrapolation between mouse and human.After demonstrating different patterns of p53 LOH by Southern blotting, we are currently examining residual chromosome 11 heterozygosity in N5 generation C57BL/6 and 129/Sv alleles (C57BL/6 backcross strain) in order to better understand the mechanism of LOH. Three distinct patterns of LOH of LOH have been detected in the C57BL/6 p53 haploinsufficient mouse exposed to model carcinogens: 1) complete loss at each chromosome 11 SSLP loci, 2) LOH at each chromosome 11 but on a background of heterozygosity and, 3) LOH on a background of heterozygosity and linked to Trp53.LOH was common among the phenolphthalein-induced lymphomas and benzene-induced sarcoma. LOH was sporadic among the p-cresidine-induced bladder carcinomas. We contend that the mechanism underlying the difference between the lymphoma and sarcoma LOH profiles is related to the actions of the individual chemical or the pathophysiology of the specific tissue. We considered the possibility that normal cell contamination was the source of the background heterozygosity detected in the sarcomas. However, wildtype contamination appeared unlikely because the amount of background heterozygosity was consistent among the eight sarcomas examined. We speculate that the background heterozygosity is more likely related to the pathophysiology of the specific tissue. Efficient culling of damaged cells is consistent with a profile of complete LOH and the p53-dependent apoptotic potential of the thymus. It is not known if the mesothelium from which the sarcomas arose is less efficient in this regard. The background heterozygosity in the sarcomas was consistent with tumor heterogeneity. Therefore, loss of Trp53 was not prerequisite for the induction of benzene-induced sarcomagenesis. In contrast, Trp53 occurred in the lymphomas prior to clonal expansion as evidenced by the lack of background heterozygosity. Finding that a complete copy of chromosome 11 was lost suggested that, in lymphomas and sarcomas, Trp53 was lost through a mechanism involving dysfunctional segregation. A complete copy of chromosome 11 was also retained in these tumors. This may indicate the clastogenic actions of phenolphthalein and benzene was secondary. The LOH profiles of the p- cresidine-induced bladder tumors showed some tumors do retain a truncated copy of chromosome 11. Finding only sporadic loss of Trp53 suggested loss was not prerequisite for initiation of cresidine-induced bladder carcinogenesis. The possibility that loss of Trp53 was masked by normal cell contamination in some bladder tumors was eliminated from consideration since p53 (+/-) and p53 (+/+) templates were easily distinguishable (Figure 1, C). In the bladder tumors, Trp53 loss appeared on a background of heterozygosity, consistent with loss during late stages when genomic instability is generalized. However, loss of Trp53 was not insignificant in the bladder tumors. Selection for cells that lost Trp53 did occurred since LOH at SSLP markers was limited to loci closely linked to Trp53. - allele loss, loss of heterozygosity, p53, environmental carcinogens, neoplasia, mutagenesis, carcinogenesis, benzene, p-cresidine, phenolphthalein